Orthostatic intolerance is the most prevalent autonomic disorder in the United States and the most common autonomic manifestation in the chronic fatigue syndrome (CFS). CFS is a common disorder of unknown cause that incapacitates young individuals in their most productive years. There is evidence that orthostatic intolerance plays a role in the fatigue of some these patients. The long-term objectives of the project are to delineate the pathophysiology and pathogenesis of orthostatic intolerance in patients with chronic fatigue; to investigate the role of orthostatic intolerance in producing the symptoms of fatigue; to use this information to institute physiologically appropriate therapeutic interventions; and thereby decrease the symptoms of fatigue. There is evidence that some patients with POTS have a restricted autonomic neuropathy (neuropathic POTS) while others have POTS unassociated with an autonomic neuropathy. The pathophysiological consequences of these two variants of POTS are not fully understood, however, it is proposed that nitric oxide availability may differ in these two subtypes. Specifically, neuropathic POTS patients may have increased nitric oxide availability whereas patients with non-neuropathic POTS may have decreased nitric oxide availability. It is not known whether nitric oxide abnormalities are merely a biological marker in POTS patients or whether the abnormalities have hemodynamic and pathophysiological significance. It is also not known whether these pathophysiological differences underlie the unsatisfactory response to therapeutic intervention in POTS patients. The Specific Aims of the application are: in two separate experiments, we will increase and decrease nitric oxide availability, and examine the autonomic cardiovascular effects of this intervention in neuropathic and non- neuropathic POTS. We will also, in two separate therapeutic interventions, increase and decrease sympathetic tone and examine the autonomic cardiovascular effects, fatigue scores, and quality of life in response to these interventions. We anticipate that the responses to changes in nitric oxide availability and the therapeutic interventions will be different in the two POTS subtypes. Public Health Significance: Orthostatic intolerance (the postural tachycardia syndrome; POTS) is the most common autonomic manifestation in patients with chronic fatigue. We will subdivide patients with POTS in to those with and with out neuropathy and determine the role played by nitric oxide in these two subgroups. We will measure the response to therapy and the role played by neuropathy and nitric oxide in determining this response. [unreadable] [unreadable] [unreadable]